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Multi-modal Proteomic Characterization of Lysosomal Function and Proteostasis in Progranulin-Deficient Neurons

ABSTRACT: Progranulin (PGRN) is a lysosomal protein involved in various neurodegenerative diseases. Over 70 mutations discovered in the GRN gene all result in reduced expression of PGRN protein. However, the detailed molecular function of PGRN within lysosomes and the impact of PGRN deficiency on lysosomal biology remain unclear. Here we leveraged multi-faceted proteomic techniques to comprehensively characterize how PGRN deficiency changes the molecular and functional landscape of neuronal lysosomes.

INSTRUMENT(S): Orbitrap Fusion Lumos, QExactive HFX

ORGANISM(S): Homo Sapiens (ncbitaxon:9606) Mus Musculus (ncbitaxon:10090)

SUBMITTER: Ling Hao

PROVIDER: MSV000091323 | MassIVE | Sun Feb 19 09:56:00 GMT 2023

SECONDARY ACCESSION(S): PXD040251

REPOSITORIES: MassIVE

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Multi-modal Proteomic Characterization of Lysosomal Function and Proteostasis in Progranulin-Deficient Neurons

Project description:Progranulin (PGRN) is a lysosomal protein involved in various neurodegenerative diseases. Over 70 mutations discovered in the GRN gene all result in reduced expression of PGRN protein. However, the detailed molecular function of PGRN within lysosomes and the impact of PGRN deficiency on lysosomal biology remain unclear. Here we leveraged multi-faceted proteomic techniques to comprehensively characterize how PGRN deficiency changes the molecular and functional landscape of neuronal lysosomes.

2023-02-18 | MSV000091322 | MassIVE

Deficiency of the frontotemporal dementia gene GRN results in gangliosidosis

Project description:Haploinsufficiency of GRN causes frontotemporal dementia (FTD). The GRN locus produces progranulin (PGRN), which is cleaved to lysosomal granulin polypeptides. The function of lysosomal granulins and why their absence causes neurodegeneration are unclear. Here we discover that PGRN-deficient human cells and murine brains, as well as human frontal lobes from GRN-mutation FTD patients have increased levels of gangliosides, glycosphingolipids that contain sialic acid. In these cells and tissues, levels of lysosomal enzymes that catabolize gangliosides were normal, but levels of bis(monoacylglycero)phosphates (BMP), lipids required for ganglioside catabolism, were reduced with PGRN deficiency. Our findings indicate that granulins are required to maintain BMP levels to support ganglioside catabolism, and that PGRN deficiency in lysosomes leads to gangliosidosis. Lysosomal ganglioside accumulation may contribute to neuroinflammation and neurodegeneration susceptibility observed in FTD due to PGRN deficiency and other neurodegenerative diseases.

2022-09-18 | PXD035889 | Pride

Loss of TREM2 reduces hyperactivation of progranulin deficient microglia but not lysosomal pathology

Project description:GRN haploinsufficiency causes frontotemporal lobar degeneration and results in microglial hyperactivation, lysosomal dysfunction and TDP-43 deposition. To understand the contribution of microglial hyperactivation to pathology we evaluated genetic and pharmacological approaches suppressing TREM2 dependent transition of microglia from a homeostatic to a disease associated state. Trem2 deficiency in Grn KO mice led to a reduction of microglia activation. To explore antibody-mediated pharmacological modulation of TREM2-dependent microglial states, we identified antagonistic TREM2 antibodies. Treatment of macrophages from GRN-FTLD patients with these antibodies allowed a complete rescue of elevated levels of TREM2 together with increased shedding and reduction of TREM2 signaling. Furthermore, antibody-treated PGRN deficient hiMGL showed dampened microglial hyperactivation, reduced TREM2 signaling and phagocytic activity, however, lack of rescue of lysosomal dysfunction. Similarly, lysosomal dysfunction, lipid dysregulation and glucose hypometabolism of Grn KO mice were not rescued by TREM2 ablation. Furthermore, NfL, a biomarker for neurodegeneration, was elevated in the Grn/Trem2 KO. These findings suggest that microglia hyperactivation is not necessarily contributing to neurotoxicity, and instead demonstrates that TREM2 exhibits neuroprotective potential in this model.

2021-07-30 | GSE181135 | GEO

Loss of TMEM106B potentiates lysosomal and FTLD-like pathology in progranulin deficient mice [neuroinflammation panel]

Project description:Polygenic risk factors influence onset and progression of neurodegenerative diseases, but are difficult to be functionally explored in isolation. Single nucleotide polymorphisms (SNPs) in TMEM106B increase the risk for frontotemporal lobar degeneration (FTLD) of GRN mutation carriers. Currently, it is not clear if progranulin (PGRN) and TMEM106B are synergistically linked and if a gain or a loss-of-function of TMEM106B is responsible for the increased disease risk of patients with PGRN haploinsufficiency. We therefore compared behavioral abnormalities, gene expression patterns, lysosomal activity and TDP-43 pathology in single and double knockout animals. Grn–/–/Tmem106b–/– mice showed a strongly reduced life span and massive motor deficits. Gene expression analysis revealed an upregulation of molecular signatures characteristic for disease associated microglia and autophagy. Dysregulation of maturation of lysosomal proteins as well as a pronounced accumulation of ubiquitinated proteins and wide spread p62 deposition suggest that proteostasis is impaired. Moreover, while single Grn–/– knockouts only occasionally showed TDP-43 pathology, the double knockout mice exhibit robust deposition of phosphorylated TDP-43. Thus, a loss-of-function of TMEM106B may enhance the risk for GRN-associated FTD by reduced protein turnover in the lysosomal/autophagic system.

2020-07-25 | GSE155066 | GEO

Loss of TMEM106B potentiates lysosomal and FTLD-like pathology in progranulin deficient mice [neuropathology panel]

2020-07-25 | GSE155065 | GEO

Loss of TREM2 reduces hyperactivation of progranulin deficient microglia but not lysosomal pathology [14 months]

2021-10-08 | GSE185510 | GEO

Gene expression profile of brain tissue from wildtype and GRN knock-out mice treated with an AAV driving expression of PTV-Progranulin in the liver

Project description:PGRN is involved in lysosomal function and is expressed in the brain. Grn knock-out (KO) mice develop several pathologies including lysosomal lipi accumulation, gliosis and neurodegeneration. Here we seek to determine if we can rescue Grn KO pathologies with a peripherally delivered AAV, that targets the liver, and drives expression of full length PGRN fused to a mouse TfR binding scFv (AAV(L):bPGRN. The PGRN fusion protein expressed by this AAV (8D3:PGRN), is brain penetrant. To study this, Grn KO mice were given a single IV injection of either saline or AAV(L):bPGRN at 4 months of age. After 8 months when the mice were 12 months of age, brain samples were collected and bulk RNA sequencing was performed to assess correction of transcriptional changes. Grn wild type (WT) mice treated with saline were also included as a control.

2024-04-19 | GSE260606 | GEO

Granulins rescue inflammation, lysosome dysfunction, and neuropathology in a mouse model of progranulin deficiency

Project description:In this study, we investigate whether individual granulin subunits derived from the precursor protein progranulin are beneficial. We test this by asking if delivery of a single granulin to the brains of a preclinical model of FTD-GRN Grn-/-mice is sufficient to ameliorate disease-like phenotypes. We performed intracerebroventricular injections of recombinant adeno-associated virus (rAAV2/1) encoding granulin-2, granulin-4, full-length PGRN or GFP in neonatal Grn+/+ and Grn-/- mice. Following AAV injections, mice were aged for 12 months, tissues collected, and analyzed. Quantitative proteomics of the thalamus identified lysosomal function and neuroinflammation as pathways ameliorated by the expression of granulins. Biochemical markers of lysosomal dysfunction, neuroinflammation, and disease-like pathology were assessed via immunoblot and immunohistochemistry. We found that both granulin-2 and granulin-4 rescue markers of lysosomal dysfunction and neuroinflammation in cortical, hippocampal, and thalamic tissue.

2024-10-15 | PXD041095 | Pride

Multi-omics Evaluation of Human iPSCs and iPSC-derived Neurons

Project description:The granulin (GRN) gene stands out as a prominent player in frontotemporal degeneration (FTD). Progranulin (PGRN) is a protein encoded by the GRN gene. Mutations in the GRN gene leading to PGRN deficiency are associated with lysosomal storage diseases and various neurodegenerative diseases. Despite the significance of GRN function, the specific impact of GRN-/- condition on diverse biomolecules such as proteins, lipids, and metabolites remain unclear. This study employs a multi-omics approach, integrating proteomics, lipidomics, and metabolomics analyses for comprehensively unraveling the molecular alterations by GRN-/- condition. Proteins, lipids, and metabolites were obtained from the same sample using a single extraction method. Our result reveals distinct molecular profiles between iPSC and neurons, emphasizing upregulated synaptic proteins such as SYN1, SYT1, VAMP2, and SV2A in proteomics, decreased cardiolipin (CL) containing 16:0 and 18:1 acyl chain in lipidomics, and shifts in acetylcholine and amino acid in metabolomics. Furthermore, the GRN-/- condition induces significant alterations across the proteome, lipidome, and metabolome of induced pluripotent stem cells (iPSC) and iPSC-derived neurons, unveiling unique metabolic pathways. Although this study was conducted at a whole cell level, this comprehensive perspective contributes to our understanding of the intricate interplay among proteins, lipids, and metabolites in neurodevelopment and neurodegenerative diseases.

2023-11-13 | MSV000093388 | MassIVE

Crohn's disease risk variant in GPR65 alters lysosomal function

Project description:Using an siRNA screen we identify a role for GPR65 in the defense against intracellular pathogens. Epithelial cells and macrophages lacking GPR65 exhibited impaired clearance of intracellular bacteria as well as an accumulation of aberrant phagosomes and lysosomes. Transcriptional profiling revealed changes in genes associated with lysosomal function. Bone marrow-derived macrophages from WT or Gpr65-/- mice were harvested for RNA analysis.

2016-06-15 | E-GEOD-69445 | biostudies-arrayexpress

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